Therapies for treating pulmonary diseases

ABSTRACT

This invention relates to treating pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase-4 inhibitor with a beta-adrenergic bronchodilator.

This is a 371 of PCT/US 99/19332 filed Aug. 24, 1999 which claimspriority to U.S. Provisional Application No. 60/097,973 filed Aug. 26,1998.

AREA OF THE INVENTION

This invention relates compositions and methods for preventing orreducing the onset of symptoms of pulmonary diseases, or treating orreducing the severity of pulmonary diseases. In particular it relates tocompositions and methods for treating pulmonary diseases mediated byphosphodiesterase 4 (PDE4) by administering a PDE4 inhibitor with otherpharmaceutically active agents which affect pulmonary function.

BACKGROUND OF THE INVENTION

Identification of novel therapeutic agents for treating pulmonarydiseases is made difficult by the fact that multiple mediators areresponsible for the development of the disease. Thus, it seems unlikelythat eliminating the effects of a single mediator could have asubstantial effect on all three components of chronic asthma. Analternative to the “mediator approach” is to regulate the activity ofthe cells responsible for the pathophysiology of the disease.

One such way is by elevating levels of cAMP (adenosine cyclic3′,5′-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973]. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺²-ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3′-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has been shown that a distinct cyclic nucleotide phosphodiesterase(PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airwaysmooth muscle and inflammatory cells. [Torphy, “PhosphodiesteraseIsozymes: Potential Targets for Novel Anti-asthmatic Agents” in NewDrugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989].Research indicates that inhibition of this enzyme not only producesairway smooth muscle relaxation, but also suppresses degranulation ofmast cells, basophils and neutrophils along with inhibiting theactivation of monocytes and neutrophils. Moreover, the beneficialeffects of PDE IV inhibitors are markedly potentiated when adenylatecyclase activity of target cells is elevated by appropriate hormones orautocoids, as would be the case in vivo. Thus PDE IV inhibitors would beeffective in the lung, where levels of prostaglandin E₂ and prostacyclin(activators of adenylate cyclase) are elevated. Such compounds wouldoffer a unique approach toward the pharmacotherapy of bronchial asthmaand possess significant therapeutic advantages over agents currently onthe market.

In addition, it could be useful to combine therapies in light of thefact that the etiology of many pulmonary diseases involves multiplemediators. In this invention there is presented the combination of a PDE4 inhibitor and an inhaled long-acting beta agonist for treatingpulmonary diseases, particularly COPD or asthma.

SUMMARY OF THE INVENTION

In a first aspect this invention relates to a method for treating apulmonary disease by administering to a patient in need thereof aneffective amount of a PDE 4 inhibitor and a long-acting beta adrenergicbronchodilator either in a single combined form, separately, orseparately and sequentially where the sequential administration is closein time, or remote in time.

In a second aspect this invention relates to a composition for treatinga pulmonary disease comprising an effective amount of a PDE4 inhibitor,an effective amount of a long-acting beta adrenergic bronchodilator anda pharmaceutically acceptable excipient.

In a third aspect this invention relates to a method for preparing acomposition which is effective for preventing the symptoms of treating apulmonary disease which method comprises mixing an effective amount of aPDE4 inhibitor and a long-acting beta adrenergic bronchodilator with apharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

The combination therapy contemplated by this invention comprisesadministering a PDE4 inhibitor with a long-acting beta adrenergicbronchodilator to prevent onset of a pulmonary disease event or to treatan existing condition. The compounds may be administered together in asingle dosage form. Or they may be administered in different dosageforms. They may be administered at the same time. Or they may beadministered either close in time or remotely, such as where one drug isadministered in the morning and the second drug is administered in theevening. The combination may be used prophylactically or after the onsetof symptoms has occurred. In some instances the combination(s) may beused to prevent the progression of a pulmonary disease or to arrest thedecline of a function such as lung function.

The PDE4 inhibitor useful in this invention may be any compound that isknown to inhibit the PDE4 enzyme or which is discovered to act in asPDE4 inhibitor, and which are only PDE4 inhibitors, not compounds whichinhibit other members of the PDE family as well as PDE4. Generally it ispreferred to use a PDE4 antagonists which has an IC₅₀ ratio of about 0.1or greater as regards the IC₅₀ for the PDE IV catalytic form which bindsrolipram with a high affinity divided by the IC₅₀ for the form whichbinds rolipram with a low affinity.

PDE inhibitors used in treating inflammation and as bronchodilators,drugs like theophylline and pentoxyfyllin, inhibit PDE isozymesindiscriminently in all tissues. These compounds exhibit side effects,apparently because they non-selectively inhibit all 5 PDE isozymeclasses in all tissues. The targeted disease state may be effectivelytreated by such compounds, but unwanted secondary effects may beexhibited which, if they could be avoided or minimized, would increasethe overall therapeutic effect of this approach to treating certaindisease states. For example, clinical studies with the selective PDE 4inhibitor rolipram, which was being developed as an antidepressant,indicate it has psychotropic activity and produces gastrointestinaleffects, e.g., pyrosis, nausea and emesis.

It turns out that there are at least two binding forms on human monocyterecombinant PDE 4(hPDE 4) at which inhibitors bind. One explanation forthese observations is that hPDE 4exists in two distinct forms. One bindsthe likes of rolipram and denbufylline with a high affinity while theother binds these compounds with a low affinity. The preferred PDE4inhibitors of for use in this invention will be those compounds whichhave a salutary therapeutic ratio, i.e., compounds which preferentiallyinhibit cAMP catalytic activity where the enzyme is in the form thatbinds rolipram with a low affinity, thereby reducing the side effectswhich apparently are linked to inhibiting the form which binds rolipramwith a high affinity. Another way to state this is that the preferredcompounds will have an IC₅₀ ratio of about 0.1 or greater as regards theIC₅₀ for the PDE 4catalytic form which binds rolipram with a highaffinity divided by the IC₅₀ for the form which binds rolipram with alow affinity. Examples of such compounds are:

Papaverine—1-[(3,4-dimethoxyphenyl )methyl]-6,7-dimethoxyisoquinoline;

Trequinsin—2,3,6,7-tetrahydro-2-(mesitylimino)-9,10-dimethoxy-3-methyl-4H-primido[6,1-α]isoquinoline-4-one;

Dipyrimadole—the generic name for2,2′,2″,2′″-[(4,8-dipiperldinopyrimido[5,4-d]pyrimidine-2-6-diyl)dinitrilo]tetraethanol;

(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2pyrrolidone;

(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,

3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone,

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];

(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate;

(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate,

Most preferred are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are trequinsin, dipyridamole, andpapaverine. Compounds such ascis-[cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate],2-carbomethoxy-4-cyano-4-(3cyclopropylmethoxy-4-diflouromethoxyphenyl)cyclohexan-1-one,andcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]are examples of structures which bind preferentially to the low affinitybinding site and which have an IC₅₀ ratio of 0.1 or greater.

Reference is made to co-pending U.S. application Ser. No. 08/456,274filed May 31, 1995 and its parent a PCT application published Jan. 05,1995 as W)95/00139 for a methods and techniques which can be used toidentify compound which have a high/low IC₅₀ ratio of 0.1 or greater asreferred to in the proceeding paragraph. This co-pending application,U.S. Ser. No. 08/456,274 is incorporated herein by reference as if setout in full herein.

The several specific compounds set out above which do not have a genericor trade name can be made by the processed described in co-pending U.S.patent applications U.S. Ser. No. 862,083 filed Oct. 30, 1992; U.S. Ser.No. 862,111 filed Oct. 30, 1992; U.S. Ser. No. 862,030 filed Oct. 30,1992; and U.S. Ser. No. 862,114 filed Oct. 30, 1992 or their progeny orU.S. patent(s) claiming priority from one or more of these applications.Each of these applications or related patents is incorporated herein bypreference in full as if se t out in this document.

The beta adrenergic bronchodilator, β₂-adreneric agonists really, usedin this invention will be a long-acting compound. Any compound of thistype can be used in this combination therapy approach. By long-lastingit is meant that the drug will have an affect on the bronchi that lastsaround 6 hours or more, up to 12 hours in some instances. To illustrate,certain resorcinols such as metaproterenol, terbutaline, and fenoterolcan be combined with a PDE4 inhibitor in the practice of this invention.Further examples of useful beta adrenergic bronchodilators is the likesof two structurally related compounds, albuterol {racemic(∝¹-[(t-butylamino)methyl]-4-hydroxy-m-xylene-∝,∝′-diol)} and formoterol{(R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]ethyl]phenyl]formamide}.

Metaproterenol is the subject of U.S. Pat. No. 3,341,594 and iscommercially available under the trade names of Alotec, Alupent,Metaprel or Novasmasol. Terbutaline is described in U.S. Pat. No.3,938,838 and is available commercially as Brethine from Novartis. Thepreparation of fenoterol is described in U.S. Pat. No. 4,341,593. It issold under several trade names, including Airum, Berotec, Dosberotec andPartusisten. Albuterol is sold under the trademark Proventil® bySchering Corporation. Formoterol is described in U.S. Pat. No. 3,994,974and is available commercially under the names Atock and Foradil.

A preferred combination therapy is that of formoterol andcis-[cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate].

These drugs, the beta agonists, are usually administered as an oral ornasal spray or aerosol, or as an inhaled powder. Usually these drugs arenot administered systemically or by injection. The PDE4 inhibitors canbe administered orally or by inhalation (orally or internasally). Thisinvention contemplates either co-administering both drugs in onedelivery form such as an inhaler, that is putting both drugs in the sameinhaler. Alternatively one can put the PDE4 inhibitor into pills andpackage them with an inhaler that contains the beta agonist.Formulations are within the skill of the art.

It is contemplated that both active agents would be administered at thesame time, or very close in time. Alternatively, one drug could be takenin the morning and one later in the day. Or in another scenario, onedrug could be taken twice daily and the other once daily, either at thesame time as one of the twice-a-day dosing occurred, or separately.Preferably both drugs would be taken together at the same time.

The foregoing statements and examples are intended to illustrate theinvention, not to limit it. Reference is made to the claims for what isreserved to the inventors hereunder.

What is claimed is:
 1. A composition for treating a pulmonary diseasecomprising an effective amount of a PDE4 inhibitor, an effective amountof a long-acting beta adrenergic bronchodilator and a pharmaceuticallyacceptable excipient.
 2. A method for preparing a composition which iseffective for preventing the symptoms of, or treating a pulmonarydisease which method comprises mixing an effective amount of a PDE4inhibitor and a long-acting beta adrenergic bronchodilator with apharmaceutically acceptable excipient.
 3. A method for treating apulmonary disease by administering to a patient in need thereof aneffective amount of a PDE 4inhibitor and a long-acting beta adrenergicbronchodilator either in a combined form, separately, or separately andsequentially where the sequential administration is close in time orremote in time.
 4. The method of claim 3 wherein the PDE4 inhibitor iscis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate]and the beta agonist is formoterol.